The main and long term[unreadable] goal of this application is to understand the mechanism of action of[unreadable] bactericidal antibodies in Borrelia infections. A number of monoclonal[unreadable] antibodies have been discovered that can kill Borrelia burgdorferi without[unreadable] the assistance of complement, and the Fab fragments of the antibodies have[unreadable] the same bactericidal activity. Earlier studies showed that these[unreadable] antibodies function by lysis of the outer membrane in a Ca++ dependent[unreadable] medium process. This application is based on the hypothesis that complement[unreadable] independent bactericidal antibodies represent a novel and fundamental[unreadable] mechanism of host resistance in infections with Borrelia, and possibly in[unreadable] infections with other bacteria.[unreadable] The Research Plan is based on three underlying hypotheses that support the[unreadable] main goal of this application to characterize the mechanisms by which[unreadable] bactericidal antibodies can destroy Borrelia spp. The first approach will[unreadable] be to examine the antibodies themselves for possible catalytic properties[unreadable] which could result in a breakdown of the antigen leading to changes in the[unreadable] physical association of the antigen with other outer membrane molecules.[unreadable] The possibility that the antibodies could induce unique conformational[unreadable] changes in their antigens, which in turn could affect the topology and[unreadable] integrity of the outer membrane will also be evaluated. The second approach[unreadable] will be to test the hypothesis that the antibody-antigen complex induces the[unreadable] activation of lytic enzymes through an outer membrane signal transduction[unreadable] mechanism. Specifically, the identification and role of lipases and[unreadable] phospholipases in Borrelia will be evaluated. Such enzymes exist in these[unreadable] organisms and should be involved in the lysis of the outer membrane. If[unreadable] this mechanism of killing Borrelia is found to occur, it will represent a[unreadable] novel, and overlooked form of host defense. The third approach will be to[unreadable] test the possibility that bactericidal antibodies are a major form of host[unreadable] defense in Borrelia infections. Passive immunization studies will be[unreadable] conducted with the bactericidal antibodies in complement deficient[unreadable] (transgenic) mice to determine their role in preventing infection in a[unreadable] complement independent manner. Other studies will be involved in raising[unreadable] targeted bactericidal antibodies to antigens expressed in vivo. The[unreadable] possibility that the bactericidal antibodies may select more invasive[unreadable] phenotypes will also be evaluated.[unreadable]